CD247 Modulates Blood Pressure by Altering T-Lymphocyte Infiltration in the Kidney
The CD3 ζ chain (CD247), a gene involved in T-cell signaling, has been shown to associate with blood pressure in human genetic studies. To test the functional role of CD247 in hypertension and renal disease, zinc-finger nucleases targeting CD247 were injected into Dahl salt-sensitive (SS/JrHsdMcwi) embryos. The resulting 11-bp frameshift deletion in exon 1 of CD247 led to a predicted premature stop codon. Western blotting confirmed the absence of CD247 protein in the thymus, and flow cytometry (n=5–9 per group) demonstrated that the mutant rats (CD247–/–) have a >99% reduction in circulating CD3+ T cells compared with littermate controls (CD247+/+). Studies were performed on age-matched, littermate male, CD247+/+ and CD247–/– rats fed a 4.0% NaCl diet for 3 weeks. The infiltration of CD3+ T cells into the kidney after high salt was significantly blunted in CD247–/– (1.4±0.4×105 cells per kidney) when compared with that in the CD247+/+ (8.7±2.0×105 cells per kidney). Accompanying the reduced infiltration of T cells, mean arterial blood pressure was significantly lower in CD247–/– than in CD247+/+ (134±1 versus 151±2 mm Hg). As an index of kidney disease, urinary albumin and protein excretion rates were significantly reduced in CD247–/– (17±1 and 62±2 mg/d, respectively) when compared with that in CD247+/+ (49±3 and 121±5 mg/d, respectively). Glomerular and renal tubular damage were also attenuated in the CD247–/–. These studies demonstrate that functional T cells are required for the full development of Dahl salt-sensitive hypertension and indicate that the association between CD247 and hypertension in humans may be related to altered immune cell function.
- Received August 7, 2013.
- Revision received August 21, 2013.
- Accepted November 13, 2013.
- © 2013 American Heart Association, Inc.